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Objective Epithelioid trophoblastic tumor (ETT) is a rare form of gestational trophoblastic neoplasm which is distinct based on its development from intermediate trophoblast cells and nodular growth pattern. The aim of this study is to describe a case series from a single institution with a review of the literature to better understand the clinical characteristics and outcomes for patients with ETT. Methods A retrospective review was performed using the IRB approved New England Trophoblastic Disease Center (NETDC) database from 1998 to 2014. Eight patients were identified of which seven had complete records. Follow-up data was obtained from the longitudinal medical records. Results Four (57.1%) patients presented with vaginal bleeding and two (28.6%) patients were asymptomatic at presentation. Three (42.9%) patients had extrauterine disease. All three patients with extrauterine disease who received chemotherapy had stable or progressive disease at follow-up. Only two (29%) patients who presented with non-metastatic disease and underwent hysterectomy were alive with no evidence of disease. The mean interval following antecedent pregnancy was 104 months. All patients with an interval > 4 years demonstrated stable or progressive disease despite intensive chemotherapy. Two patients with non-metastatic disease who declined hysterectomy developed stable or progressive disease despite chemotherapy. Conclusions This series highlights several features of ETT including the potential for asymptomatic presentation of extrauterine disease. The series also demonstrates chemoresistance, even with multi-agent therapy and a poor prognosis with extrauterine disease and an interval greater than 4 years following the antecedent pregnancy suggesting that surgery remains critical in disease control. [ABSTRACT FROM AUTHOR]

Objective: We reviewed cases of placental site trophoblastic tumors from the New England Trophoblastic Disease Center (NETDC) database from 1982-1999 in an effort to identify prognostic factors for recurrent disease., Methods: A chart review was performed utilizing patients identified from the NETDC database. Data obtained included patient age at diagnosis, antecedent pregnancy, duration and extent of disease, presenting symptoms, pre- and posttreatment hCG levels, diagnostic and therapeutic procedures, treatment and outcome of patients. Statistical analysis was performed using Student's t test and chi(2) test when appropriate., Results: Thirteen patients were identified. All ultimately underwent hysterectomy although initial treatment of 1 patient was uterine resection. There were 5 recurrences (43%)--3 among the 9 patients who had no metastases on presentation (33%) and 2 of 3 patients who presented with metastases (66%). The 5 patients who recurred were among 8 who had received peri- or postoperative chemotherapy (62.5%). Treatment of recurrences included continued or alternate chemotherapy, radiotherapy, and/or excision of locally recurrent disease. Follow up time averaged 56.2 months (range 12-182 months). One of the 4 patients receiving chemotherapy < or =1 week after hysterectomy recurred, whereas all 4 patients who received chemotherapy 3 weeks or more after hysterectomy recurred. Uterine tumor volume was significantly greater, 154.1 cm(3), in patients with initial metastases versus 42.3 cm(3) in patients without initial metastases (P = 0.04). Mitotic index (P = 0.04) was significantly increased in patients who developed recurrent disease., Conclusion: High mitotic index appears to be an adverse prognostic indicator for recurrence. Hysterectomy remains the mainstay of treatment. Chemotherapy is indicated for patients with metastases and may be indicated when the mitotic index is >5 mitoses/10 HPF. Radiation treatment may play a role in recurrent disease but must be evaluated on a case-by-case basis., (Copyright 2001 Academic Press.)

Objective: The aim of this study was to determine the role of parental factors that may relate to the pathogenesis of molar pregnancy., Methods: A retrospective review of six patients who had a molar pregnancy with at least two different partners at New England Trophoblastic Disease Center between 1965 and March 1999 was performed., Results: A total of 34 pregnancies with 20 different partners were observed in 6 patients. These pregnancies resulted in 15 (44.1%) hydatidiform moles, 8 (23.5%) term live births, 7 (20.6%) therapeutic abortions, 3 (8.8%) spontaneous abortions, and 1 preterm delivery. While 5 patients had a molar pregnancy with 2 different partners, 1 patient had a molar pregnancy with 3 different partners. Two patients developed persistent postmolar gestational trophoblastic tumor in 3 (20.0%) of the 15 episodes of molar pregnancy. Three of the male partners reported a total of 7 healthy children from prior relationships., Conclusion: The experience in these six patients suggests that a primary oocyte problem may contribute to the development of molar pregnancy., (Copyright 1999 Academic Press.)

Objective: To determine the outcome of pregnancies occurring before completion of human chorionic gonadotropin follow-up in patients treated with chemotherapy for gestational trophoblastic tumor., Methods: Retrospective record review of patients with gestational trophoblastic tumor who conceived before standard hCG follow-up was completed during 1973-1998., Results: Forty-three patients treated for gestational trophoblastic tumors conceived before human chorionic gonadotropin follow-up was completed. The antecedent pregnancy was complete mole in 31 (72.1%) and partial mole in 12 (27. 9%) patients. Of the 43 patients, 39 (90.7%) had stage I, 1 had stage II, and 3 had stage III disease. The mean interval from human chorionic gonadotropin remission to new pregnancy was 6.3 months (range 1-11 months). Ten patients underwent elective termination and four patients were lost to follow-up. Of the remaining 29 patients, 22 (75.9%) had term live births, 3 (10.3%) had preterm delivery, 3 had spontaneous abortion, and 1 (3.5%) had a repeat mole. Two cases of fetal anomalies were detected; one was inherited polydactyly and the other was hydronephrosis. One patient developed choriocarcinoma with lung involvement and underwent cesarean section at 28 weeks; a normal fetus was delivered and no choriocarcinoma was detected in the placenta., Conclusion: Pregnancies occurring in patients treated for gestational trophoblastic tumor before standard human chorionic gonadotropin follow-up is completed may continue under close clinical surveillance since the majority have a favorable outcome. However, patients should also be advised of the low but important risk of delayed diagnosis in case tumor relapse develops during early subsequent pregnancy., (Copyright 1999 Academic Press.)

Objective: To evaluate the efficacy and safety of etoposide, methotrexate, and actinomycin D (EMA) as primary and secondary therapy for gestational trophoblastic tumor (GTT)., Methods: In a retrospective study, the medical records of all patients with middle-risk metastatic GTT or nonmetastatic choriocarcinoma receiving primary EMA and patients with GTT resistant to single-agent regimens treated with secondary EMA were reviewed. Hematologic toxicity was graded using WHO criteria., Results: Seven patients received primary EMA with 5 (67%) achieving remission. Twenty-two patients with resistance to single-agent regimens received secondary EMA with 21 (95%) achieving remission. The most acute hematologic toxicity was grade 1 or 2. Only 2 of 90 EMA cycles were associated with grade 4 toxicity requiring hospital admission., Conclusion: Although EMA effectively induces remission with minimal acute hematologic toxicity in the primary and secondary therapy of GTT, recently published data regarding secondary tumors associated with etoposide exposure should restrict its use to patients who absolutely require etoposide to achieve remission.

The current study investigates the clinical characteristics of patients with partial molar pregnancy who developed persistent gestational trophoblastic tumor (GTT). Between January 1979 and January 1989, 16 of 240 (6.6%) patients, who were followed for partial mole, developed persistent GTT. Fifteen (94%) patients were diagnosed as having a missed abortion before evacuation and only 1 patient presented with excessive uterine size and theca lutein ovarian cysts and was felt to have molar disease. No patient presented with toxemia, hyperemesis, or hyperthyroidism. All 16 patients developed nonmetastatic GTT. Fifteen patients achieved complete remission with methotrexate-citrovorum factor and only 1 patient required combination chemotherapy to attain remission. None of the patients had histologic evidence of choriocarcinoma. Patients with partial mole who developed persistent GTT did not have clinical or pathological characteristics that distinguished them from other patients with partial mole. All patients with partial mole should be followed with measurement of hCG levels to assure gonadotropin remission.

Thirty-two patients with nonmetastatic gestational trophoblastic tumors were treated with methotrexate infusion and folinic acid and the results of this therapy were compared to our prior experience with the 8-day methotrexate-folinic acid regimen. Complete remission was achieved in 22 of 32 (68.7%) patients treated with methotrexate infusion and 147 of 163 (90.2%) patients treated with the 8-day regimen (P less than 0.01). One course of chemotherapy induced complete remission in 19 (86.3%) patients treated with methotrexate infusion and 121 (82.2%) patients treated with the 8-day regimen. All 10 patients resistant to methotrexate infusion later achieved remission with other chemotherapy. Following methotrexate infusion, no patient developed myelosuppression, hepatotoxicity, or alopecia. Efforts should continue to identify new chemotherapeutic protocols that maximize remission rates and minimize toxicity and hospitalization.

The current study reviews post-term choriocarcinoma at the New England Trophoblastic Disease Center (NETDC) in order to expand knowledge of its clinical features. Between June 1965 and June 1981, 366 patients with persistent gestational trophoblastic disease were managed at the NETDC and 15 (4.1%) of these patients had choriocarcinoma following term pregnancy. Post-term choriocarcinoma has a propensity for early metastasis with frequent involvement of the liver and brain. Metastases were detected in 13 (86.7%) patients with post-term choriocarcinoma at the time of diagnosis. Seven patients (53.8%) with metastatic post-term choriocarcinoma had hepatic and/or cerebral involvement. Complete remission was achieved in both patients with nonmetastatic disease and in 8 (61.5%) patients with metastatic disease. When the time interval from the antecedent term delivery to diagnosis was less than 4 months, 7 (87.5%) of 8 patients achieved complete remission. The 5 patients who died from post-term choriocarcinoma all had hepatic and/or cerebral involvement. Patients with post-term choriocarcinoma should undergo a meticulous metastatic evaluation and if metastases are detected these patients should be treated with primary combination chemotherapy and with the selective use of irradiation and surgical therapy.

Pelvic ultrasonography was performed in 33 patients with persistent gestational trophoblastic disease (GTD) and the sonographic findings were compared in all patients with laparoscopic findings and histologic material from endometrial curettage and/or hysterectomy. Ultrasonography indicated trophoblastic uterine involvement in 17 patients (51.5%) and the ultrasound interpretation was histologically confirmed in all 17 patients by endometrial curettage and/or hysterectomy. Among the 16 patients in whom the uterus appeared normal by ultrasound, endometrial curettings demonstrated scanty fragments of trophoblastic tumor in 6 patients (37.5%). Furthermore, in all 16 patients in whom the uterus appeared normal by ultrasound, laparoscopy also revealed no uterine abnormalities. Ultrasonography appears to be accurate in detecting extensive trophoblastic uterine involvement and helpful in identifying resistant uterine foci. Pelvic ultrasonography should be an integral part of the pretreatment assessment of patients with persistent GTD.

Modified triple chemotherapy (MAC III: methotrexate with citrovorum factor, actinomycin D, and cyclophosphamide) was administered as primary treatment to 14 patients with high-risk metastatic gestational trophoblastic tumors (GTT). Ten (71.4%) patients attained complete remission with 1 to 4 courses of MAC III (mean = 2.7 courses). Three of the remaining patients subsequently achieved remission with the modified Bagshawe regimen or vinblastine, bleomycin, and cis-platinum. Following 38 courses of MAC III, moderate hepatotoxicity (SGOT greater than or equal to 150 U) developed after 1 (2.6%) course. Marked thrombocytopenia (platelets less than 50,000/mm3) and marked granulocytopenia (granulocytes less than 500/mm3) developed after 7 (18.4%) and 19 (50%) of the courses, respectively. Platelet transfusions were administered after 4 (10.5%) courses of MAC III and no patient required granulocyte transfusions. MAC III is an effective alternative treatment for patients with high-risk metastatic GTT.

Murine stage-specific embryonic antigens (SSEA-1, SSEA-3) are well characterized oncofetal antigens and have been identified in several human tumors. The current study was undertaken to determine the localization of SSEA-1 and SSEA-3 in hydatidiform mole, normal human placenta, and gestational choriocarcinoma. SSEA-3 did not react with any cellular components in hydatidiform moles, normal placentas, or choriocarcinoma cell lines. SSEA-1 was detectable in two human gestational choriocarcinoma cell lines, but not in the trophoblastic cells of 10 hydatidiform moles or in nine normal placentas between 6 weeks and term gestation. Therefore, according to this oncofetal marker system, the trophoblast in hydatidiform mole is more like normal trophoblast than gestational choriocarcinoma.

Methotrexate and folinic acid was administered as primary therapy in 185 patients with gestational trophoblastic disease between 1974 and 1984. Methotrexate and folinic acid induced complete remission in 147 (90.2%) of 163 patients with nonmetastatic disease and in 15 (68.2%) of 22 patients with low-risk metastatic disease. Sustained remission was achieved in 132 (81.5%) patients following only one course of chemotherapy. All patients with methotrexate resistance subsequently achieved remission with Actinomycin D or combination chemotherapy. Methotrexate when administered with folinic acid was associated with granulocytopenia, thrombocytopenia, and hepatotoxicity in 11 (5.9%), 3 (1.6%), and 26 (14.1%) patients, respectively. The human chorionic gonadotropin (hCG) regression curve served as a reliable guide for the administration of chemotherapy and enabled the attainment of a high remission rate while limiting chemotherapy exposure. Methotrexate and folinic acid achieves an excellent therapeutic outcome with limited chemotherapy exposure and effectively limits systemic toxicity.

The current study was undertaken to characterize the expression of trophoblast-lymphocyte cross-reactive antigens on normal, molar, and malignant trophoblast. A panel of monoclonal antibodies directed against lymphoid cell markers were tested in immunofluorescence assay on cryostat sections of placenta and mole and on monolayers of choriocarcinoma cells. NKH-1, a monoclonal antibody to natural killer cells, reacted with both molar and placental villous trophoblast and with two choriocarcinoma cell lines. NKH-2, a monoclonal antibody reactive with a subset of natural killer cells, did not react with placental villous trophoblast but reacted with molar villous trophoblast in three of five moles tested and with both choriocarcinoma cell lines. B5, a monoclonal antibody which reacts with activated B cells, reacted with both choriocarcinoma cell lines but did not react with normal placental or molar trophoblast. MY7, a monoclonal antibody to myeloid colony-forming cells, reacted with only one of the choriocarcinoma cell lines. Trophoblast-lymphocyte cross-reactive antigens may be important in the immunobiology of gestational trophoblastic disease by modulating interactions between the trophoblast and the maternal immune system.

The current study was undertaken to examine reactivity patterns of well-characterized anti-human sperm monoclonal antibodies with normal placenta, complete hydatidiform mole (HM), and gestational choriocarcinoma (CCA). Two anti-human sperm monoclonal antibodies (MA2 and MA7) out of a panel of 14 reacted with human CCA cell lines but did not react with the trophoblast of 4 HM or 4 normal placentas from 13 weeks to term gestation in immunofluorescence and absorption tests. Therefore, in terms of expressing these sperm-embryonic antigens, the trophoblast of HM is more like normal placental trophoblast than CCA. The relationships among normal placenta, HM, and CCA may be better understood by continued studies on the pattern of expression of additional embryonic antigens in these three gestational tissues.

The course of 51 patients with high-risk metastatic gestational trophoblastic tumor was reviewed. The clinical characteristics and therapy of patients who died were compared to patients who attained remission to identify parameters that are associated with treatment failure. The presence of liver, brain, or intestinal metastases and the failure of prior chemotherapy were found to portend a poor prognosis (P less than 0.001, P less than 0.05). Other high-risk factors such as markedly elevated HCG levels, time interval greater than 4 months from the antecedent pregnancy to treatment, and post-term choriocarcinoma were not independently associated with treatment failure. The mean prognostic score and the mean number of high-risk factors for patients who died were 13 and 3, as compared to 7 and 2, respectively, for patients who achieved remission (P less than 0.001, P less than 0.001). Alternative intensive chemotherapy regimens need to be developed to improve remission rates in patients with liver, brain, or intestinal metastases, failed prior chemotherapy, or a high prognostic score.

Cell-free villous fluid from healthy and necrotic molar villi did not contain detectable soluble HLA Class I (HLA-A,B,C) antigens; therefore, HLA sensitization of the maternal host is probably not attributable to shedding of HLA antigens by viable or degenerating HLA-positive stromal cells. The method developed for this study, a combination of immunoprecipitation and Western blot techniques, employed specific antibodies for positive identification of the HLA heavy chain. The pathogenesis of complete molar pregnancy may be better understood through further study of the mechanisms of HLA sensitization of the maternal host and the host's response to these foreign antigens.